Evgeny Gladilin

An adaptive irregular grid approach for 3D deformable image registration.

Deformable registration is an important application in medical image analysis and processing. We propose a physics-based parametric approach for deformable image registration, where non-rigid transformations are computed using an irregular grid of control points distributed within the image domain. The image is modelled as a three-dimensional (3D) homogeneous infinite elastic medium. It is assumed that a Gaussian-shaped force is applied at every control point, where the strengths, directions and influence areas of the forces as well as the positions of the control points are considered as free parameters whose optimization leads to maximization of the similarity measure between the images to be registered. For optimization, a computationally efficient Levenberg-Marquardt method is used. The proposed approach has certain advantages over traditional landmark-based methods or the registration methods based on regular grids, for example B-splines, since comparable results can be achieved by using less control points. Experimental results with 3D clinical images demonstrate that our method is capable of successfully coping with complex registration tasks.

The role of Vimentin in Regulating Cell Invasive Migration in Dense Cultures of Breast Carcinoma Cells

Cell migration and mechanics are tightly regulated by the integrated activities of the various cytoskeletal networks. In cancer cells, cytoskeletal modulations have been implicated in the loss of tissue integrity and acquisition of an invasive phenotype. In epithelial cancers, for example, increased expression of the cytoskeletal filament protein vimentin correlates with metastatic potential. Nonetheless, the exact mechanism whereby vimentin affects cell motility remains poorly understood. In this study, we measured the effects of vimentin expression on the mechano-elastic and migratory properties of the highly invasive breast carcinoma cell line MDA231. We demonstrate here that vimentin stiffens cells and enhances cell migration in dense cultures, but exerts little or no effect on the migration of sparsely plated cells. These results suggest that cell-cell interactions play a key role in regulating cell migration, and coordinating cell movement in dense cultures. Our findings pave the way toward understanding the relationship between cell migration and mechanics in a biologically relevant context.

A comparison between BEM and FEM for elastic registration of medical images

The aim of medical image registration is to bring different images into the best possible spatial correspondence in order to obtain complementary information for clinical applications. When using physically-based techniques for image registration the transformation of images is typically obtained as the solution of partial differential equations of continuum mechanics. Because of the complexity of real boundary conditions, these equations can usually be solved with the help of numerical techniques only. One standard numerical method is the boundary element method (BEM) which allows to compute the solution exclusively through boundary integration. This paper investigates the applicability of BEM for registration of medical images and quantitatively assesses its advantages and disadvantages in comparison to the previously used finite element method (FEM).

Nonlinear elastic model for image registration and soft tissue simulation based on piecewise St. Venant-Kirchhoff material approximation

Linear elastic model widely applied for simulation of soft tissue deformations in biomedical imaging applications is basically limited to the range of small deformations and rotations. Thus, computation of large deformations and rotations using linear elastic approximation and its derivatives is associated with substantial error. More realistic modeling of mechanical behavior of soft tissue requires handling of different types of nonlinearities. This paper presents a framework for more accurate modeling of deformable structures based on the St. Venant-Kirchhoff law with the nonlinear Green-Lagrange strain tensor and variable material constants, which considers both material and geometric nonlinearities. We derive the governing partial differential equation of nonlinear elasticity, which represents consistent extension of the Lame-Navier PDE of linear elasticity, and describe two alternative numerical schemes for solving this nonlinear PDE via the Newtons and fixed point method, respectively. The results of our comparative studies demonstrate the advantages of nonlinear elastic model for accurate computing of large deformations and rotations in comparison to the linear elastic approximation.

On the embryonic cell division beyond the contractile ring mechanism: experimental and computational investigation of effects of vitelline confinement, temperature and egg size.

Embryonic cell division is a mechanical process which is predominantly driven by contraction of the cleavage furrow and response of the remaining cellular matter. While most previous studies focused on contractile ring mechanisms of cytokinesis, effects of environmental factors such as pericellular vitelline membrane and temperature on the mechanics of dividing cells were rarely studied. Here, we apply a model-based analysis to the time-lapse imaging data of two species (Saccoglossus kowalevskii and Xenopus laevis) with relatively large eggs, with the goal of revealing the effects of temperature and vitelline envelope on the mechanics of the first embryonic cell division. We constructed a numerical model of cytokinesis to estimate the effects of vitelline confinement on cellular deformation and to predict deformation of cellular contours. We used the deviations of our computational predictions from experimentally observed cell elongation to adjust variable parameters of the contractile ring model and to quantify the contribution of other factors (constitutive cell properties, spindle polarization) that may influence the mechanics and shape of dividing cells. We find that temperature affects the size and rate of dilatation of the vitelline membrane surrounding fertilized eggs and show that in native (not artificially devitellinized) egg cells the effects of temperature and vitelline envelope on mechanics of cell division are tightly interlinked. In particular, our results support the view that vitelline membrane fulfills an important role of micromechanical environment around the early embryo the absence or improper function of which under moderately elevated temperature impairs normal development. Furthermore, our findings suggest the existence of scale-dependent mechanisms that contribute to cytokinesis in species with different egg size, and challenge the view of mechanics of embryonic cell division as a scale-independent phenomenon.

Detection of non-uniform multi-body motion in image time-series using saccades-enhanced phase correlation

Unsupervised analysis of time-series of live-cell images is one of the important tools of quantitative biology. Due to permanent cell motility or displacements of subcellular structures, microscopic images exhibit intrinsic non-uniform motion. In this article, we present a novel approach for detection of non-uniform multi-body motion which is based on combination of the Fourier-phase correlation with iterative probing target and background image regions similar to the strategy known from saccadic eye movements. We derive theoretical expressions that yield plausible explanation why this strategy turns out to be advantageous for tracking particular image pattern. Our experiments with synthetic and live-cell images demonstrate that the proposed approach is capable of accurately detecting non-uniform motion in synthetic and live-cell images.

Quantification of substrate and cellular strains in stretchable 3D cell cultures: an experimental and computational framework

The mechanical cell environment is a key regulator of biological processes . In living tissues, cells are embedded into the 3D extracellular matrix and permanently exposed to mechanical forces. Quantification of the cellular strain state in a 3D matrix is therefore the first step towards understanding how physical cues determine single cell and multicellular behaviour. The majority of cell assays are, however, based on 2D cell cultures that lack many essential features of the in vivo cellular environment. Furthermore, nondestructive measurement of substrate and cellular mechanics requires appropriate computational tools for microscopic image analysis and interpretation. Here, we present an experimental and computational framework for generation and quantification of the cellular strain state in 3D cell cultures using a combination of 3D substrate stretcher, multichannel microscopic imaging and computational image analysis. The 3D substrate stretcher enables deformation of living cells embedded in bead‐labelled 3D collagen hydrogels. Local substrate and cell deformations are determined by tracking displacement of fluorescent beads with subsequent finite element interpolation of cell strains over a tetrahedral tessellation. In this feasibility study, we debate diverse aspects of deformable 3D culture construction, quantification and evaluation, and present an example of its application for quantitative analysis of a cellular model system based on primary mouse hepatocytes undergoing transforming growth factor (TGF‐β) induced epithelial‐to‐mesenchymal transition.

Image- and model-based analysis of constitutive properties of cellular structures

Determination of constitutive properties of cells is important for quantitative description of cellular mechanics. Existing approaches to mechanical cell manipulation are based on experimental techniques that do not allow unsupervised analysis of large number of cells and/or probing of intracellular structures that are not directly exposed to external loads. Alternatively, mechanical behavior of cellular matter can be studied in time-series of microscopic images. In this work, we present an image- and model-based framework for determination of constitutive properties of living cells. Our experimental studies demonstrate application of this approach for quantitative analysis of cellular mechanics on the basis of image data assessed by different experimental techniques, including microplate stretching, optical stretching and contactless cellular deformation induction using cytoskeleton-disrupting drugs.

On validation of non-physical techniques for elastic image registration

Non-physical techniques for elastic image registration such as different spline-based optimization methods are often applied in biomedical applications for image normalization w.r.t. non-rigid transformations. Since mechanical properties of biological structures to be registered are usually unknown, a “ground truth”validation of the results of image registration is not possible. This article presents a framework for the validation of elastic image registration techniques by a direct comparison of displacement fields vs analytical or numerical reference solutions of customizable boundary value problems. The proposed procedure enables an easy handling of material parameters, domain shapes and boundary conditions, and provides a flexible benchmark-tool for quantitative validation of elastic image registration algorithms.

Motion detection and pattern tracking in microscopical images using phase correlation approach

High-throughput live-cell imaging is one of the important tools for the investigation of cellular structure and functions in modern experimental biology. Automatic processing of time series of microscopic images is hampered by a number of technical and natural factors such as permanent movements of cells in the optical field, alteration of optical cell appearance and high level of noise. Detection and compensation of global motion of groups of cells or relocation of a single cell within a dynamical multi-cell environment is the first indispensable step in the image analysis chain. This article presents an approach for detection of global image motion and single cell tracking in time series of confocal laser scanning microscopy images using an extended Fourier-phase correlation technique, which allows for analysis of non-uniform multi-body motion in partially-similar images. Our experimental results have shown that the developed approach is capable to perform cell tracking and registration in dynamical and noisy scenes, and provides a robust tool for fully-automatic registration of time-series of microscopic images.